This invention relates to the administration of proteins by adsorption from the lungs. In particular, it is concerned with providing therapeutic, sustained doses of growth hormones or cytokines to the bloodstream without irritating or otherwise damaging lung tissue.
Drug delivery by pulmonary absorption from particles such as aerosols has met with considerable success in several instances of localized delivery to lungs as the drug target tissue, most notably the use of beta adrenergic antagonists in the treatment of asthma. Other drugs that have been administered in this fashion include corticosteroids and cromolyn sodium. On the other hand, the administration of aminoglycoside antibiotics, antiviral drugs and anti-cancer drugs for systemic action by this route has only met with spotty success. In some cases, lack of delivery to the blood stream was attributed to inability of the drug to pass through the alveolar epithelium. In other cases the drug was found to be irritating and bronchoconstrictive (Juliano, 1984, xe2x80x9cPharm. Ther.xe2x80x9d, 24:355-365). At this time it is not possible to reasonably predict in advance that any given drug will be nonirritating or will be adsorbed through the lungs in an amount sufficient to be therapeutically useful.
Similarly, extensive studies have been conducted on the pulmonary absorption of proteins and polypeptides. While size, lipophobicity, and possibly other poorly characterized features of such molecules appear to create a substantial barrier to their absorption into the blood stream (Juliano, op cit; Egan, 1983, xe2x80x9cAm. Rev. Resp. Dis.xe2x80x9d 127(5) Pt. 2 537-539; Hogg et al., 1979, xe2x80x9cFed. Proc.xe2x80x9d 38(2):197-201), there remains considerable disagreement about protein permeability from the alveoli into the blood under ordinary conditions. For example, studies with albumin or horse radish peroxidase (HRP) are illustrative.
Dominguez et al. (xe2x80x9cLab. Invest.xe2x80x9d 16(6):905 [1967]) observe that the alveolar wall is only xe2x80x9cslightly permeablexe2x80x9d to albumin. Similarly, earlier workers found no pulmonary absorption of homologous plasma albumin at all (Drinker et al., 1947 xe2x80x9cJ. Exp. Med.xe2x80x9d 86:7), while other demonstrated absorption of albumin only from lung subsections hyperinflated in excess of 40 cm H2O pressure; the same pressure applied to the total lung did not produce protein permeability (Egan et al., 1982, xe2x80x9cJ. Appl. Physiol.xe2x80x9d 53:121). Newborn lambs were found to be capable of pulmonary albumin absorption, but only for a brief period postpartum (Egan et al., 1984, xe2x80x9cPed. Res.xe2x80x9d 18(6):566). Finally, Bensch et al. (xe2x80x9cSciencexe2x80x9d 157:1204-1206 [1967]) report the rapid absorption of instilled solutions of radioactively labelled albumin or gamma globulin across the pulmonary air-tissue barrier. More than two thirds of the administered polypeptides could be accounted for in the blood of the test animals after 24 hours. These authors also report the work of others (Drinker et al., op cit) to the effect that removal of lower molecular weight proteins from the lumin of the alveoli occurs only after degradation of the molecules, notwithstanding that Bensch et al. did not detect degradation of albumin or gamma globulin.
Bensch et al. (xe2x80x9cYale J. Biol. Med.xe2x80x9d 43:236-241 [1971]) later observed (based on similar studies with HRP) that macromolecules may cross the air-blood barrier by being transported directly into the pulmonary capillary blood in the pinocytotic vesicles of the membranous pneumocyte and endothelial cells. However, the Bensch et al. experiments were conducted by instilling HRP into the lungs in the form of an aqueous solution.
Conner et al. (xe2x80x9cFundamental and Appl. Toxicologyxe2x80x9d 5:99-104 [1985]) instilled a solution of HRP into the trachea of experimental animals after exposure to zinc oxide particles, suggesting that absorption of this protein was a function of pathological effects by zinc oxide. This was consistent with the report by Hogg et al., op cit. that the bronchial epithelium is normally nonpermeable to proteins unless damaged in some way, such as by cigarette smoke, ether, antigens, histamine, or methacholine.
Other polypeptide probes besides albumin, gamma globulin and HRP have been used in the study of pulmonary absorption. These include microperoxidase, equine cytochrome c, equine myoglobin, bovine lactoperoxidase and human myeloperoxidase (Schneeberger, 1978, xe2x80x9cFed. Proc.xe2x80x9d 37(11):2471), superoxide dismutase or catalase (Padmanabhan et al., 1985, xe2x80x9cAm. Rev. Respir. Dis.xe2x80x9d 132 (1):164-167), and ferritin (Richardson et al., 1976, xe2x80x9cLab. Invest.xe2x80x9d 35(4):307). None of these agents, however, has been employed in a systemic therapeutic context, i.e. delivered in the expectation of achieving a therapeutic dosage at a desired site distal from the lungs per se.
U.S. Pat. No. 4,476,116 proposes delivering human growth hormone or interferon by intranasal absorption of a nasal spray containing the protein and a chelating agent. Since particles of 5 mm or greater are removed in the nasopharyngeal region (Juliano et al.) it must be concluded that an effective nasal spray would contain aerosol particles having at least this mean diameter. Similarly, EP 122036 describes a powdered composition for intranasal administration of growth hormone or interferon wherein at least 90% of the particles had an effective diameter of 10 to 250 microns. The minimum diameter was established with the object to avoid introducing the particles into the lungs.
Intranasal administration of growth hormone or interferons is undesirable because of dosage variability, side effects such as nasal irritation, extremely poor polypeptide permeability into the blood stream and polypeptide degradation by normal nasal microorganisms. Of course, these polypeptides have been conventionally administered by injection or infusion. This delivery route suffers from obvious deficiencies, the most glaring being the requirement for regular growth hormone injections in children or, in the case of interferons being employed for the treatment of malignancies, an absence of a healthy vasculature for catheterization of the patients. An improved method for the administration of these proteins is needed.
Accordingly, it is an object herein to obviate the need for injections or infusions of certain polypeptides.
It is a further object herein to reduce the frequency of administration of certain polypeptides by providing sustained release from pulmonary tissue.
It is another object to deliver therapeutically effective doses of certain polypeptides without therapeutically significant degradation of the polypeptides or the use of agents that lead to irritation of the bronchi, epithelium or other pulmonary tissue.
These and other objects of the invention will be apparent to the ordinary artisan from the specification as a whole.
The foregoing objects are accomplished by providing a method for delivering to the blood stream of a patient a therapeutic dose of a polypeptide selected from the group of growth factors and cytokines, which method comprises delivering a therapeutically effective dose of the polypeptide into the lungs of the patients. A device is provided for accomplishing this method that comprises reservoir means for storing the polypeptide; a therapeutic dosage form of the polypeptide disposed in the reservoir means; dispersing means for forming in a gas a suspension of particles comprising the polypeptide wherein the size of the particles is sufficiently small to permit their penetration into the alveoli of the patient""s lungs upon inhalation; means for transporting the polypeptide to the dispersing means; and means for delivering the particle suspension to alveoli of the patient""s lungs.
An advantage with respect to the delivery of therapeutic doses of these particular polypeptides is that they are delivered systemically by pulmonary absorption without pathological effects on the lungs or a requirement for an epithelial irritant or absorption enhancing agent such as ether, zinc oxide, antigens, histamine, methacholine, water soluble amphophilic steroids, bile salts such as sodium glycocholate, lower alkyl ethers of cellulose, chelating agents or water absorbing-water insoluble substances such as polyvinyl pyrrolidone, sodium carboxymethyl cellulose, polyacrylates and the like.